The purpose of this project is to identify the determinants of type 2 diabetes and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for type 2 diabetes have been studies. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Hyperinsulinemia, estimated by total immunoreactive insulin, is a characteristic feature of Pima Indians. In a study of its components (true insuiln, intact proinsulin, and des 31,32 proinsulin) in Pimas, Asians, and whites, it was determined that nondiabetic Pimas are truly hyperinsulinmeic. The proportions of insulin percursors in th serum were similar in the three ethnic groups, suggesting that the higher risk of type 2 diabetes in Pimas is not due to differences in insulin secretion or processing. In diabetic subjects from all three ethnic groups, fasting insulin concentrations were higher and the incremental insulin concentrations following a glucose challenge were lower than in nondiabetic subjects, consistent with the hypothesis that insulin resistance and impaired secretion following a challenge, but not absolute insulin deficiency, underlie the disease. The longitudinal study of glucose tolerance was used to evaluate the ability of fasting and post-load plasma glucose concentrations to predict diabetes as defined by different diagnostic criteria (WHO and ADA). Both fasting and post-load glucose concentrations were highly predictive of diabetes defined by either criterion, indicating that the fasting glucose (the only measure required by the ADA criteria) is useful not only as a diagnostic criterion for diabetes but also as a risk indicator for diabetes.